The effect of the histidine decarboxylase inhibitor brocresine (NSD-1055) on gastric acid secretion in rats

The effect of the histidine decarboxylase inhibitor brocresine (NSD-1055) given by mouth, intraperitoneally or intravenously on tetragastrin-, histamine- and bethanechol-stimulated gastric acid secretion was examined in rats. Intravenous injection of brocresine slightly reduced the tetragastrin-stimulated secretion. Histamine-stimulated secretion was markedly increased by both intraperitoneal and intravenous injection of brocresine but it had no effect on the bethanechol-stimulated secretion. It was concluded that either histidine decarboxylase is not effectively inhibited by brocresine or any inhibition induced does not affect gastric acid secretion. The enhanced histamine-stimulated secretion points towards an inhibition of diamine oxidase by brocresine.     

The effect of phloxin on bethanechol and histamine stimulated gastric acid secretion in rats

Summary The effect of phloxin (Na salt of tetrabromo-tetrachlorofluorescein) on histamine- and bethanechol-stimulated gastric acid secretion was studied in anaesthetized rats. Concentrations of phloxin, equimolar with those of the stimulants, depressed the secretory response to histamine and had no influence on the bethanechol effect. The results suggest that histamine is not involved in the events triggered by bethanechol which stimulate gastric acid secretion in rats.Supported by the Deutsche Forschungsgemeinschaft and the Gesellschaft der Freunde der Universität Tübingen.     

Inhibitors of histidine decarboxylase decrease basal gastric acid secretion in the rat

We examined the ability of two specific inhibitors of histidine decarboxylase, (s)-alpha-fluoromethylhistidine (FMHd) and (s)-alpha-fluoromethylhistamine (FMHm), to inhibit basal gastric acid secretion. The two highest doses of FMHd administered, 50 and 100 mg/kg, decreased basal gastric acid secretion and total secretion volume but did not affect intraluminal pH. FMHm decreased gastric acid secretion, raised intraluminal pH, and to a lesser degree decreased total secretion volume. Neither compound changed the severity of gastric ulcers produced by cold restraint stress.     

Effects of prostaglandin E1 on acid secretion, mucosal histamine content and histidine decarboxylase activity in rat stomach

1. Prostaglandin E(1) inhibits basal and pentagastrin-stimulated gastric acid secretion. The mechanism of this action is not clear. One possible explanation might be that prostaglandin E(1) interferes with the local release or synthesis of histamine which has been proposed as the mediator of the effects of gastrin on the parietal cell.2. A single injection of prostaglandin E(1) did not affect mucosal histamine content or histidine decarboxylase activity in the rat stomach. Pentagastrin lowered the histamine content and activated the histidine decarboxylase to the same extent in prostaglandin E(1)-pretreated and in control rats. We conclude therefore that the inhibitory effect of prostaglandin E(1) on basal and pentagastrin-stimulated acid secretion is not caused by inhibition of histamine release or histamine synthesis.3. Repeated injections of prostaglandin E(1) resulted in a significant elevation of the gastric histidine decarboxylase activity in normal but not in antrectomized rats. Conceivably, this increase in enzyme activity is secondary to prostaglandin E(1)-induced inhibition of acid secretion, which will stimulate release of gastrin due to the rise in intragastric pH.     

Centrally applied histamine increases gastric acid secretion in rats

Summary Administration of 10–100 g of histamine into the lateral cerebral ventricle of anaesthetized rats stimulated gastric acid secretion in a dose-dependent manner, while subcutaneous (s. c.) injections of the same doses produced clearly less pronounced increases in the acid output. In vagotomized rats only a marginal response to histamine given into the lateral ventricle was observed. When injected into the third cerebral ventricle the doses of histamine needed for the stimulation of gastric acid secretion were 1–10 g, the effect being totally abolished by vagotomy. The results indicate that histamine is capable of stimulating gastric acid secretion by a central, vagal-dependent mechanism.Send offprint requests to J. Puurunen at the above address     

Studies on the inhibition of histidine decarboxylase, aromatic-L-amino acid decarboxylase and acid secretion by brocresine and its metabolites

Brocresine (NSD 1055) is rapidly metabolized in vivo. The probable metabolites are 4-bromo-3-hydroxy-benzyl alcohol, 4-bromo-3-hydroxy-benzoic acid and 4-bromo-3-hydroxy-hippuric acid. Brocresine and these metabolites inhibit both rat fetal and rat gastric histidine decarboxylase (l-histidine carboxylase, EC 4.1.1.22) in vitro with a molar I₅₀ of about 10^?8, 10^?4, lO^?3 and 10^?5, respectively, for both enzymes. Brocresine and the metabolites also inhibit aromatic-l-amino acid decarboxylase (3,4-dihydroxy-l-phenylalanine carboxylase EC 4.1.1.26) from hog kidney and rat gastric mucosa in vitro with a molar I₅₀ of about 10^?7, 10^?4, 10^?3 and 10^?3, respectively, for both enzymes. Brocresine, the alcohol metabolite and the acid metabolite inhibited rat gastric histidine decarboxylase after intraperitoneal administration of 200 $\text{mg}\text{kg}$, whereas the hippurate was only weakly inhibitory. All four compounds inhibited gastric acid secretion in the pylorus-ligated rat, but the acid and hippurate were only moderately inhibitory. The reaction of hemoglobin with brocresine to form methemoglobin readily explains the rapid disappearance of the inhibitory activity of the drug.     

The stimulatory effect of forskolin on gastric acid secretion in rats

Adenylate cyclase is involved in the histamine pathway of the parietal cell. We therefore studied the effect of forskolin, a direct activator of the membrane-bound adenylate cyclase, on gastric acid secretion in anaesthetized rats. Forskolin in the range of 0.1-1 mg/kg i.v. caused a dose-dependent stimulation of acid secretion. Higher doses were not tolerated. The duration of action of the forskolin-induced acid secretion was also dose-related. The combined infusion of forskolin (0.3 mg/kg per h i.v.) and histamine at a low rate (0.5 mg/kg per h i.v.) produced a maximal stimulation of acid secretion which was comparable to that with a histamine infusion of 10 mg/kg per h i.v. without forskolin. Administration of desglugastrin at a low rate (10 micrograms/kg per h i.v.) plus forskolin by i.v. infusion produced similar results. In contrast, infusion of carbachol (3 micrograms/kg per h i.v.) together with forskolin caused only an additive effect on acid secretion. Including an isobutyl-methyl-xanthine (IBMX) i.v. injection of 3 mg/kg at the beginning of the forskolin infusion (0.3 mg/kg per h i.v.) produced an acid output after 60 min which was approximately 50% of the maximal stimulation during a histamine (10 mg/kg per h i.v.) infusion. The IBMX/forskolin-induced stimulation was completely inhibited by 0.5 mg/kg omeprazole i.v. while the equipotent antisecretory dose (during histamine stimulation) of cimetidine caused only a weak decrease in acid output.     

Effect of a sulphated glycopeptide on rat gastric acid secretion stimulated by histamine, bethanechol, pentagastrin and dibutyryl cyclic AMP

The antisecretory activity of a semisynthetic sulphated glycopeptide (GLPS) was studied in rats in which the secretion rates of gastric acid were detennined on the perfused stomach preparation. GLPS at 1 mg/kg i.v. reduced the hypersecretory effect of dibutyryl cyclic AMP, histamine, pentagastrin, bethanechol but not of theophylline.     

The effect of clonidine on gastric acid secretion in rats and dogs

Summary The effect of clonidine on gastric acid secretion was investigated using rats and dogs. In the stomach lumen perfused rat basal gastric acid secretion was increased by clonidine in the anaesthetized rat but inhibited in the conscious animal. Clonidine also reduced the basal gastric acid secretion in rats with chronic gastric fistula, (ED₅₀ 12 g/kg p.o.). In addition, gastric secretion stimulated by insulin hypoglycaemia was inhibited by clonidine in anaesthetized stomach lumen perfused rats and in conscious dogs with gastric fistula. In the rat gastric secretion stimulated by electrical vagus stimulation was inhibited as well. However, clonidine had no effect on the gastric acid secretion stimulated by carbachol in stomach lumen perfused rats and in dogs with denervated fundic pouch.These results suggest that the inhibition of gastric acid secretion by clonidine probably is due to an inhibition of acetylcholine release at the vagus nerve endings. Additional central gastric antisecretory effects can, however, not be excluded by this study.     

Effects of pentagastrin,histamine, carbamylcholine and catecholamines on gastric secretion,motility and emptying in the rat

We developed a simplified method for the simultaneous measurement of gastric secretion and gastric motility in the rat. By using this method, we investigated the actions of pentagastrin, histamine, carbamylcholine and catecholamines on the stomach. Carbamylcholine stimulated acid secretion and induced contraction of the stomach, but norepinephrine tended to inhibit acid secretion and induced relaxation of the stomach. Histamine induced relaxation first and then contraction after 2–5 min. Pentagastrin induced a relaxation that did not show dose dependence, but tachyphylaxis. Isoproterenol, which stimulated acid secretion in our experiments, induced relaxation of the stomach in a dose-dependent manner. We also investigated the relationship between gastric motility and gastric emptying. Carbamylcholine caused an enhancement of gastric emptying, but isoproterenol caused its suppression. Pentagastrin, histamine and norepinephrine did not affect gastric emptying. As shown in the results of our experiments, carbamylcholine caused stimulation of acid secretion, contraction of the stomach, and enhancement of gastric emptying. However, other secretagogues did not always induce contraction of the stomach or increase gastric emptying.     

Acid gastric secretory responses to histamine, crude porcine gastrin and pentagastrin in rats

The log dose-response curves for graded doses of the secretagogues porcine gastrin (a partially purified sample; the crude and its gastrin II equivalent), histamine, and a gastrin pentapeptide (pentagastrin) on the perfused stomachs of urethanized rats are parallel. On weight basis, pentagastrin is 60 times and histamine four times more active than the crude porcine gastrin preparation. The partially purified porcine gastrin sample is six times more potent than histamine but half as potent as pentagastrin. On molar basis gastrin (as the pure porcine gastrin II) has 3000 times the activity of histamine dihydrochloride and 5000 times that of the histamine base. Gastrin is 50 times more potent than pentagastrin. Gastrin and pentagastrin are more potent and have less undesirable side-effects than histamine.     

Absence of tachyphylaxis in gastric acid secretion during pentagastrin infusion

Tachyphylaxis to stimulation of gastric juice secretion during intravenous pentagastrin (PG) infusion has been reported in animal studies. We assessed the course of gastric response to PG 2 micrograms/kg/hr over eight hours in eight healthy subjects. Peak H+, pepsin, and volume secretions occurred during the second half hour of stimulation. Peak H+ output was 11.6 +/- 1.3 mmol/0.5 hr or 7.6 +/- 0.8% of the total eight-hour secretion. During subsequent half-hour collection intervals, there was no significant decline in response, and the average output was 10.3 +/- 0.4 mmol/0.5 hr (6.5 +/- 0.1%). Peak pepsin and volume secretions were respectively 10.0 +/- 1.4% (74.8 +/- 11.6 mg/0.5 hr) and 8.8 +/- 1.1% (146.3 +/- 17.4 mL/0.5 hr) of the total eight-hour secretion. Although there was a significant decline in pepsin and volume response subsequent to the peak output, the decline was not continuous, and pepsin and volume secretions were maintained, respectively, at 6.0 +/- 0.2% (46.1 +/- 2.5 mg/0.5 hr) and 6.2 +/- 0.1% (107.5 +/- 3.0 mL/0.5 hr) of the total eight-hour secretion. Our study did not demonstrate any tachyphylaxis in H+ response to continuous PG stimulation. This model appears to be a valid tool for the assessment of histamine-H2 antagonist effects on stimulated gastric juice secretion over 8 hours in humans.     

Inhibitory effect of somatostatin on gastric acid secretion in rats

Effects of somatostatin on parasympathetically induced increases in gastric acid secretion and mucosal blood flow (MBF) were studied in anesthetized rats with a gastric fistula. Intravenous infusion of small doses of somatostatin (0.1-0.5 microgram/kg/min) dose-dependently inhibited the increases in the vagally stimulated gastric acid secretion. Larger doses of somatostatin (0.5-2.5 micrograms/kg/min) also dose-dependently inhibited the bethanechol-induced gastric acid secretion. The dose of somatostatin required to inhibit the gastric acid secretion by about 50% of the preinfused control values was 0.25 microgram/kg/min for vagally stimulated acid secretion and 2.5 micrograms/kg/min for bethanechol-induced acid secretion. Thus, the inhibitory potency of somatostatin on the vagally stimulated gastric acid secretion was about 10-fold higher than that on bethanechol-induced acid secretion. Somatostatin had no effect on the increase in gastric MBF during vagus nerve stimulation or bethanechol infusion. Pretreatment with indomethacin or phentolamine had no effect on the inhibitory effect of somatostatin on the increase in gastric acid secretion during vagus nerve stimulation or bethanechol infusion. These results suggest that somatostatin exerts an inhibitory effect on gastric acid secretion by acting on the parasympathetic neurons in the gastric wall more than on the structures peripheral to the parasympathetic nerve terminals, and it reduces parasympathetically stimulated gastric acid secretion in rats. This inhibitory effect of somatostatin on the gastric acid secretion is independent of the changes in the gastric MBF and probably not related to prostaglandin-involved or alpha adrenoceptor-mediated mechanisms.     

Effects of chlorpromazine and bromolysergic acid diethylamide on gastric secretion of acid induced by histamine in rats

In anaesthetized rats in which the lumen of the stomach was perfused with 0.001 to 0.00025 N-sodium hydroxide solution and the pH of effluent fluid was recorded continuously, intravenous administration of chlorpromazine caused transient inhibition of acid secretion. After acid secretion had returned to the control level the responses to histamine were greater than those before chlorpromazine was given. Aminoguanidine, iproniazid and bromolysergic acid diethylamide also potentiated the effect of histamine on acid secretion but the initial inhibition was absent. Indirect evidence from experiments in which mixtures of aminoguanidine with chlorpromazine or bromolysergic acid diethylamide and of iproniazid with chlorpromazine or bromolysergic acid diethylamide were given, suggests that chlorpromazine and bromolysergic acid diethylamide enhance responses to histamine by inhibition of imidazole-N-methyl transferase.